1) Field of the Invention
The invention relates to an animal model of cardiovascular disease and a method of preparation and use thereof. Inter alia, it relates to a genetically engineered animal model of aortic aneurysms and methods for screening drugs using the animal model.
2) Description of Related Art
The aorta, the largest artery in the body, is responsible for pumping blood out of the heart and into the organs of the body. The aorta projects upward from the heart through the chest (thoracic aorta), and then arches downward into the abdomen (abdominal aorta). By definition, an aneurysm is a permanent dilation of the arterial wall. An aortic aneurysm is a widening, bulge, or ballooning out of a portion of the aorta, usually a weak spot in the aortic wall, typically causing the vessel to progressively expand to at least 1.5 times beyond its normal diameter of one inch.
Aortic aneurysms are commonly classified according to their anatomical location. While thoracic aortic aneurysms (TAAs) involve the ascending aorta, arch or descending aorta; abdominal aortic aneurysms (AAAs) affect the part of the aorta in the abdominal cavity. A third type involves thoracoabdominal aneurysms that originate in the descending aorta and extend to the abdominal aorta.
With gradual enlargement, the aneurysm can lead to either dissection or rupture of the aorta. Dissection is when the blood enters the wall of the aorta and splits it in two. Ninety-five percent of aortic dissections originate either within the ascending or descending aorta and fewer than 5% originate in the abdominal aorta or aortic arch. Aortic dissection is caused by a deterioration of the inner lining of the aorta. There are a number of conditions that predispose a person to develop defects of the inner lining, including high blood pressure (hypertension), Marfan's disease, Ehlers-Danlos syndrome, connective tissue diseases, and defects of heart development which begin during fetal development. A dissection can also occur accidentally following insertion of a catheter, trauma, or surgery.
Depending on the nature and extent of the dissection, death can occur within a few hours of the start of a dissection. Approximately 75% of untreated people die within two weeks of the start of a dissection. Of those who are treated, 40% survive more than 10 years. Patients are usually given long term treatment with drugs to reduce their blood pressure, even if they have had surgery.
A major problem in the management of aortic aneurysms is that the symptoms of an aortic aneurysm often do not surface until the aneurysm is quite large. However, once enlarged, the aneurysm can cause the aorta to put pressure on the surrounding organs in the chest. Clinical features may include upper back pain, coughing and wheezing, hoarse voice, difficulty swallowing, swelling (edema) in the neck or arms and Horner's syndrome (constricted pupil, drooping eyelid and dry skin on one side of the face).
Clearly, a timely diagnosis can result in early intervention and dramatic improvement in the chances for survival. However, there is no screening routine for aortic aneurysms and the mechanism(s) underlying aortic aneurysm formation are poorly understood.
Mouse models of abdominal aortic aneurysms (AAAs) have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction (see for a review Daugherty et al. Arterioscler. Thromb Vasc Biol. 2004 March; 24(3):429-34). The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Most of the mouse models of AAA are evoked either by genetically defined approaches or by chemical means. The genetic approaches are spontaneous and engineered mutations. These include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII.
An experimental murine model for thoracic aortic aneurysms (TAAs) is also described before. Ikonomidis et al. (J. Surg. Res. 2003; 115:157-63) report a model system for chemically evoked TAA in a murine system. It was found that abluminal application of CaCl2 to the thoracic aorta via left thoracotomy produces dilation, wall-thinning and disruption of mural architecture. In a related study, it was found that deletion of the TIMP-1 gene results in increased and continued progression of aneurysm formation (Ikonomidis et al. Circulation, 2004; 110(11 Suppl. 1): II1268-73).
A major drawback of the known “chemical” animal models for aneurysms is that they exhibit a large degree of variability with respect to the onset and severity of the aneurysm evoked. It appears difficult to adjust the correct dose of chemical to each individual animal, in particular when using small animals like rats and mice.